Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray. Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low.
Certain trisubstituted piperidine compounds are disclosed in U.S. Pat. No. 5,492,916 (issued Feb. 20, 1996) as being non-peptidal growth hormone secretagogues. These compounds have the ability to stimulate the release of natural or endogenous growth hormone and thus may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
Among the preferred compounds disclosed therein is the compound: ##STR2## and pharmaceutically acceptable salts thereof, in particular, the hydrochloride salt. The processes for the preparation of this compound are described in U.S. Pat. No. 5,492,916 by Morriello et al. The processes described therein proceed by preparation of a racemic 3-benzylnipecotate followed by separation of the the enantiomers at some step of the overall process. The maximum theoretical yield of optically active product by such procedures is 50%.
In accordance with the present invention there is provided a process in which the S-piperidine intermediate (S)-3-carbethoxy-3-benzylpiperidine!is prepared from optically active S-monoacid/ monoester which is obtained from the prochiral diester via an efficient esterase hydrolysis, thereby avoiding the drastic automatic loss of 50% of some intermediate. The problem with the previous procedure for the preparation of the piperidine intermediate is that a resolution of the corresponding tartrate salt via a crystallization is necessary to obtain optically active piperidine needed for the preparation of the final compound. The maximum theoretical yield of optically active material by such a procedure is 50%. ##STR3##
The advantage of the instant stereoselective hydrolysis procedure is that it provides product of high optical activity (&gt;99% ee) in high yield (80%). In contrast, for the resolution based procedure half of the material is lost as its antipode.
Some work on the enzymatic hydrolysis of disubstituted malonate diesters has been reported by Iriuchijima, Agric. Biol. Chem., 46, 1907-1910 (1982); Bjorkling et al., Tetrahedron 41, 1347-1352 (1985); Bjorkling et al., Bioorganic Chemistry, 14, 176-181 (1986); Dejeso et al., Tetrahedron Letters, 31, 653-654 (1990); and Toone et al., J. Am. Chem. Soc., 31, 653-654 (1990).